Disruption of epigenetic mechanisms and pathways of gene regulation plays an important role in a spectrum of important disease states including cancer (Mai & Altucci, 2009, Int. J. Biochem. Cell Biol. 41:199-213).
Genome-wide screening for somatic mutations in non-Hodgkin's lymphoma (NHL) has shown a high prevalence of mutations in genes/proteins involved in epigenetic regulation of gene expression. Recurrent somatic mutations in the methyltransferase protein EZH2 were found to be likely to contribute to development of NHL through increased activity of the PRC2 of which it is a constituent protein. EZH2 is a histone mark “writer” that catalyzes the trimethylation of histone H3 lysine 27 (H3K27me3). NHL tumours with EZH2 mutations have been shown to have increased activity of the PRC2 in trimethylating histone H31(27 which leads to increased suppression of gene expression and tumourgenesis (Morin, et al., 2010, Nat. Genet., 42(2): 181-185).
Overactivity and/or overexpression of EZH2 has been associated with a number of other cancers, including breast cancer, lung cancer, prostate cancer (in particular, late stage prostate cancer), multiple myeloma and cancers of the neurological system. In many cases, overactivity/overexpression of EZH2 has been associated with aggressive or drug resistant forms of these cancers. H3K27me3 marks are read by the protein CBX2.
The methyltransferase MLL2 writes activatory histone marks. This histone modification is interpreted by the reader protein BPTF. Mutations in MLL2 are also common in non-Hodgkin's lymphoma, with mutations being observed in 32% of DLBCL cases and 89% of follicular lymphomas (Morin, et al, 2011, Nature 476: 298-303). The mutational profile across MLL2 in these tumors was entirely consistent with a loss-of-function. MLL2 participates in laying down an activatory mark, H3K4me3 (Yap, et al, 2011, Blood 117:2451-2459; Sneeringer, et al, 2010, Proc. Natl. Acad. Sci. U.S.A. 107:20980-20985) and loss of this ability maintains the cells in a proliferative state, not by repression of a transcriptional program, but through the cells inability to activate a pro-differentiation transcriptional program. Mutations in MLL genes have also been found in gastric adenocarcinomas, leukemias, bladder and colorectal cancers (Gui, et al, 2011, Nat. Genet. 43:875-878; Watanabe, et al, 2011, PLoS One 6:e23320; Ziemin-van der Poel, et al, 1991, Proc. Natl. Acad. Sci. U.S.A. 88:10735-10739).
The ability of BPTF to read trimethylated H3K4 has been modulated by engineering a single tyrosine to glutamic acid substitution within the PHD finger domain of the protein, resulting in a reversal of the binding preference from trimethyl- to dimethyl-lysine in an H3K4 context (Li, et al., 2007, Molecular Cell, 28:677-691).
Inhibition or disruption of binding of histone mark readers has been reported as an approach for treating disease, including cancer. In particular, histone demethylases have been targeted for inhibition (see Rotili & Mai, 2011, Genes & Cancer, 2:663-679; International Patent Application Publication No. WO2012/071469).
International Patent Application Publication No. WO2011/143669 describes compounds and methods for disrupting the interaction of a bromodomain and extra-terminal (BET)-family protein with an acetyl-lysine modification on a histone N-terminal tail. Specifically, the compounds inhibit binding of the BET family protein to the acetyl-lysine. Uses of the compounds to treat cancer and inflammatory diseases are also described.
International Patent Application Publication No. WO2012/123119 describes in vitro methods employing biotin and strepavidin that allow for the identification of proteins interacting with histone tails and compounds that interact with such proteins.
International Patent Application Publication No. WO2012/116170 describes compounds that inhibit acetyl-lysine binding activity of the bromodomain of the CREB-binding protein (CBP).
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.